F-aza-T-dCyd (NSC801845), a Novel Cytidine Analog, in Comparative Cell Culture and Xenograft Studies with the Clinical Candidates T-dCyd, F-T-dCyd, and Aza-T-dCyd

  • Mol Cancer Ther. 2021 Apr;20(4):625-631. doi: 10.1158/1535-7163.MCT-20-0738.
Joel Morris  1 ,  Donn G Wishka  2 ,  Omar D Lopez  2 ,  Vladimir Rudchenko  3 ,  Guangfei Huang  3 ,  Sierra N Hoffman  4 ,  Suzanne Borgel  4 ,  Kyle Georgius  4 ,  John Carter  4 ,  Howard Stotler  4 ,  Mark W Kunkel  2 ,  Jerry M Collins  2 ,  Melinda G Hollingshead  2 ,  Beverly A Teicher  2
Affiliations
  • 1. Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland. [email protected].
  • 2. Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland.
  • 3. Alchem Laboratories Corporation, Alachua, Florida.
  • 4. Leidos Biomedical Laboratories, FNLCR, Frederick, Maryland.
PMID: 33811149 DOI: 10.1158/1535-7163.MCT-20-0738
Abstract

In this article, 5-aza-4'-thio-2'-β-fluoro-2'-deoxycytidine (F-aza-T-dCyd, NSC801845), a novel cytidine analog, is first disclosed and compared with T-dCyd, F-T-dCyd, and aza-T-dCyd in Cell Culture and mouse xenograft studies in HCT-116 human colon carcinoma, OVCAR3 human ovarian carcinoma, NCI-H23 human NSCLC carcinoma, HL-60 human leukemia, and the PDX BL0382 bladder carcinoma. In three of five xenograft lines (HCT-116, HL-60, and BL-0382), F-aza-T-dCyd was more efficacious than aza-T-dCyd. Comparable activity was observed for these two agents against the NCI-H23 and OVCAR3 xenografts. In the HCT-116 study, F-aza-T-dCyd [10 mg/kg intraperitoneal (i.p.), QDx5 for four cycles], produced complete regression of the tumors in all mice with a response that proved durable beyond postimplant day 150 (129 days after the last dose). Similarly, complete tumor regression was observed in the HL-60 leukemia xenograft when mice were dosed with F-aza-T-dCyd (10 mg/kg i.p., QDx5 for three cycles). In the PDX BL-0382 bladder study, both oral and i.p. dosing of F-aza-T-dCyd (8 mg/kg QDx5 for three cycles) produced regressions that showed tumor regrowth beginning 13 days after dosing. These findings indicate that further development of F-aza-T-dCyd (NSC801845) is warranted. GRAPHICAL ABSTRACT: http://mct.aacrjournals.org/content/molcanther/20/4/625/F1.large.jpg.

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